N-oxy and N-amino guanidines

ABSTRACT

The compounds are N-oxy and N-amino guanidines which are histamine H2-antagonists. A compound of this invention is N-hydroxy-N&#39;-methyl-N&#39;&#39;-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]gu anidine.

This is a division of application Ser. No. 786,729 filed Apr. 11, 1977,now U.S. Pat. No. 4,093,729 which is a division of Ser. No. 585,898filed June 11, 1975 now U.S. Pat. No. 4,034,101.

This invention relates to pharmacologically active compounds, topharmaceutical compositions comprising these compounds and to processesfor their preparation. The compounds of the invention can exist as theaddition salt but, for convenience, reference will be made throughoutthis specification to the parent compounds.

Many physiologically active substances elicit their biological actionsby interaction with specific sites known as receptors. Histamine is sucha substance and has a number of biological actions. Those biologicalactions of histamine which are inhibited by drugs commonly called"antihistamines" of which mepyramine is a typical example, anddiphenhydramine and chlorpheniramine are other examples are mediatedthrough histamine H₁ -receptors (Ash and Schild, Brit. J. Pharmac.Chemother, 27, 427, (1966)). However, other of the biological actions ofhistamine are not inhibited by `antihistamines` and actions of this typewhich are inhibited by a compound described by Black et al. (Nature,236, 385 (1972)) and called burimamide are mediated through receptorswhich are defined by Black et al. as histamine H₂ -receptors. Thushistamine H₂ -receptors may be defined as those histamine receptorswhich are not blocked by mepyramine but are blocked by burimamide.Compounds which block histamine H₂ -receptors are referred to ashistamine H₂ -antagonists.

Blockade of histamine H₂ -receptors is of utility in inhibiting thebiological actions of histamine which are not inhibited by"antihistamines". Histamine H₂ -antagonists are therefore useful, forexample, as inhibitors of gastric acid secretion, as anti-inflammatoryagents and as agents which act on the cardiovascular system, for exampleas inhibitors of the effects of histamine on blood pressure, in thetreatment of certain conditions, for example inflammation and ininhibiting the actions of histamine on blood pressure, a combination ofhistamine H₁ - and H₂ -antagonists is useful.

The compounds with which the present invention is concerned arehistamine H₂ -antagonists. The compounds may be represented by thefollowing general formula:- ##STR1## wherein R₁ represents a grouping ofthe structure shown in Formula II:-

    het -- (CH.sub.2).sub.m Z(CH.sub.2).sub.n --               FORMULA II

wherein Het is a nitrogen-containing 5 or 6 membered heterocyclic ringsuch as imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole,triazole or thiadiazole, which is optionally substituted by lower alkyl,hydroxyl, chlorine, bromine or amino; Z is sulphur or a methylene group;m is 0, 1 or 2 and n is 2 or 3 provided that the sum of m and n is 3 or4; R₂ is hydrogen, lower alkyl or a grouping of the structure shown inFormula II wherein Het, m, n and Z are as defined above; X is oxygen orNH; and R₃ is hydrogen, lower alkyl, aryl such as phenyl or arylalkylsuch as benzyl.

Throughout the present specification, by the term "lower alkyl" we meanan alkyl group containing from 1 to 4 carbon atoms.

It will be understood that the structure illustrated in Formula I isonly one of several representations and that other tautomeric forms arealso covered by the present invention.

In a preferred group of compounds X is oxygen, R₃ is hydrogen and R₂ islower alkyl. In a further preferred group R₂ is the same as R₁. In bothof these groups it is particularly preferred that m should be 1 and nshould be 2; compounds wherein Z is sulphur are also preferred; itfollows therefore that compounds wherein R₁ and/or R₂ are Het-CH₂S--(CH₂)₂ are an important part of the present invention. Het mayparticularly usefully be imidazole, thiazole, isothiazole or pyridineoptionally substituted by methyl, hydroxyl, chlorine or bromine.

A useful series of compounds are those wherein R₃ is hydrogen.

Examples of specific compounds falling within the scope of the presentinvention areN-hydroxy-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,N-hydroxy-N',N"-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,N-methoxy-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]guanidine,N-methoxy-N',N"-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,N-amino-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine,N-amino-N',N"-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidineand N-hydroxy-N'-methyl-N"-[2-((2-thiazolyl)methylthio)ethyl]-guanidine.

A method which may be used for the production of compounds of Formula Icommences from a thiourea of the Formula III:- ##STR2## Reaction of thiscompound with a lower alkyl halide of formula AY wherein A is loweralkyl and Y is halogen, e.g. methyl iodide or with lower alkanol offormula AOH in the presence of a halogen acid, HY, e.g., with methanolichydrogen, chloride yields the isothiourea of Formula IV (shown as theacid addition salt): ##STR3## wherein A, Y, R₁ and R₂ have the abovementioned significance. Treatment of this isothiourea with a compound offormula R₃ X NH₂, wherein R₃ and X have the same significance as inFormula I, yields the compounds of Formula I. This latter reaction ispreferably carried out in the presence of a base such as potassiumbicarbonate.

An alternative method which may be used for the production of compoundsof Formula I wherein X is NH consists of treating the isothiourea ofFormula IV (shown as the acid addition salt) wherein A, Y, R₁ and R₂have the above significance, with a compound of formula R₃ R₄ N.NH₂,wherein R₃ has the same significance as in Formula I and R₄ is aprotecting group such as tert-butyloxycarbonyl. This reaction ispreferably carried out in the presence of a base such as potassiumbicarbonate. The protecting group is then removed with for examplehydrochloric acid to yield the compounds of Formula I.

The thioureas of Formula III are prepared as follows:-

Starting from an amine of Formula R₁ NH₂, wherein R₁ has the samesignificance as in Formula I, reaction with carbon disulphide and alower alkyl halide or sulphate such as methyl iodide or methyl sulphategives the corresponding dithiocarbamic ester of Formula V (which will ofcourse normally exist in the form of the acid addition salt). ##STR4##wherein A is lower alkyl and subsequent reaction of this compound underalkaline conditions (e.g. in the presence of sodium ethoxide in asolvent such as ethanol) with the amine of formula R₂ NH₂, gives therequired thiourea of Formula III. Where R₁ and R₂ are the same, therequired compounds can be produced without isolation of an intermediateof Formula V by the reaction of carbon disulphide with an excess (twomoles or more) of the amine of formula R₁ NH₂, this reaction beingconveniently carried out in a solvent such as ethanol.

The compounds of Formula I block histamine H₂ -receptors, that is theyinhibit the biological actions of histamine which are not inhibited by"antihistamines" such as mepyramine but are inhibited by burimamide. Forexample, the compounds of this invention have been found to inhibithistamine-stimulated secretion of gastric acid from the lumen-perfusedstomachs of rats anaesthetized with urethane, at doses of from 0.5 to256 micromoles per kilogram intravenously. This procedure is referred toin the above mentioned paper of Ash & Schild. The activity of thesecompounds as histamine H₂ -antagonists is also demonstrated by theirability to inhibit other actions of histamine which, according to theabove mentioned paper of Ash and Schild, are not mediated by histamineH₁ -receptors. For example, they inhibit the actions of histamine on theisolated guinea pig atrium and isolated rat uterus.

The compounds of this invention inhibit the basal secretion of gastricacid and also that stimulated by pentagastrin or by food.

In addition, the compounds of this invention show anti-inflammatoryactivity in conventional tests such as the rat paw oedema test, wherethe oedema is induced by an irritant, the rat paw volume is reduced bysubcutaneous injection of doses of a compound of Formula I. In aconventional test, such as the measurement of blood pressure in theanaesthetised cat, the action of the compounds of this invention ininhibiting the vasodilator action of histamine can also be demonstrated.The level of activity of the compounds of this invention is illustratedby the effective dose producing 50% inhibition of gastric acid secretionin the anaesthetized rat (which for many of the compounds of Formula Iis from 1 to 10 micromoles per kilogram) and the dose producing 50%inhibition of histamine-induced tachycardia in the isolated guinea pigatrium.

For therapeutic use, the pharmacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with apharmaceutical carrier therefor. Such addition salts include those withhydrochloric, hydrobromic, hydriodic, sulphuric and maleic acids and mayconveniently be formed from the corresponding bases of Formula I bystandard procedures, for example by treating the base with an acid in alower alkanol or by the use of ion exchange resins to form the requiredsalt either directly from the base or from a different addition salt.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of Formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of blocking histamine H₂ -receptors whichcomprise administering a compound of Formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention. The pharmaceutical carrier employed may be, for example,either a solid or liquid. Exemplary of solid carriers are lactose, terraalba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid contained for example in an ampoule,or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the compositions in aneffective amount to block histamine H₂ -receptors. The route ofadministration may be oral or parenteral.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg.

The active ingredient will preferably be administered one to six timesper day. The daily dosage regimen will preferably be from about 150 mgto about 1500 mg.

Advantageously the composition will be made up in a dosage formappropriate to the desired mode of administration for example as atablet, capsule, injectable solution or as a cream or ointment fortopical application.

The invention is illustrated but in no way limited by the followingExamples in which all temperatures are in degrees Centigrade:

EXAMPLE IN-Hydroxy-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride.

(i) Dry hydrogen chloride gas was passed into a solution ofN-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-thiourea (73.2g) in methanol (600 ml) and the mixture was refluxed for 5 hours.Concentration and re-evaporation with isopropyl alcohol afforded acrystalline solid which was recrystallised from isopropyl alcohol-etherto giveN,S-dimethyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-isothioureadihydrochloride (96.2 g) m.p. 191°-192°. (isopropyl alcohol-ether).

(ii) A mixture of the isothiourea dihydrochloride (3.3 g) hydroxylaminehydrochloride (2.1 g), potassium hydrogen carbonate (10 g) and anhydrousdimethyl formamide (50 ml) was vigorously stirred for 4 hours at 85°.Following cooling and filtration from inorganic material the filtratewas concentrated to yield the free base and this was then dissolved in Nhydrochloric acid (40 ml) and ethanol (10 ml). Concentration andtrituration of the residual oil with isopropanol afforded a solid whichwas recrystallised from aqueous isopropyl alcohol to give the titlecompound (0.85 g) m.p. 218°-219°.

When an aqueous ethanolic solution of this dihydrochloride is passeddown a suitable ion-exchange column, for example of IRA-401 in basicform, the free base in pure form may be obtained by concentration of theeluate. Pretreatment of the column with an acid e.g., sulphuric acidleads to the production of the appropriate salt, e.g. the disulphate.

EXAMPLE 2N-Hydroxy-N,N"-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinetrihydrochloride.

(i) A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (34.0g) and carbon disulphide (7.6 g) in ethanol (250 ml) was heated underreflux for 6 hours. Concentration followed by chromatographicpurification of the product on a column of silica gel with elution byisopropyl alcohol-ethyl acetate followed by isopropyl alcohol-ethanolgave N,N'-bis-[2-(4-methyl-5-imidazolyl)methylthio)ethyl]thiourea (18g), m.p. 133°-135°.

(Found: C, 47.0; H, 6.1; N, 22.0% C₁₅ H₂₄ N₆ S₃ requires: C, 46.8; H,6.3; N, 21.9%)

(ii) The reaction ofN,N'-bis-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]thiourea (7.7 g)with ethanolic hydrogen chloride by the method described in Example 1affordedS-methyl-N,N'-bis-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]isothioureatrihydrochloride (9.0 g), m.p. 212°-215° (isopropyl alcohol).

(Found: C, 37.6; H, 5.7; N, 16.3; S, 18.6; Cl, 20.5% C₁₆ H₂₆ N₆ S₃. 3HCl requires: C, 37.8; H, 5.8; N, 16.5; S, 18.9; Cl, 20.9%).

(iii) A mixture of the isothiourea trihydrochloride (15.2 g)hydroxylamine hydrochloride (7.0 g) potassium hydrogen carbonate (16.0g) and anhydrous dimethyl formamide (150 ml) was stirred vigorously for3 hours at 90°. Following cooling, filtration and concentration theresultant free base was purified on a column of silica gel by elutionwith chloroform-methanolic ammonia. After treatment with an excess ofethanolic hydrogen chloride, the residue was dissolved in isopropanoland crystallised to give the title compound (2.1 g), m.p. 224°-225°.

(Found: C, 36.3; H, 5.6; N, 19.7; Cl, 21.3; S, 12.7%. C₁₅ H₂₅ N₇ OS₂.3HCl requires: C, 36.6; H, 5.7; N, 19.9; Cl, 21.6; S, 13.0%).

EXAMPLE 3N-Methoxy-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)-ethyl]guanidinedihydrochloride

A mixture of the isothiourea dihydrochloride from Example I(i) (6.6 g),methoxyamine hydrochloride (5.0 g), potassium hydrogen carbonate (8.0 g)and water (60 ml) was refluxed for 24 hours. Following cooling, anexcess of sodium chloride was added and the solution extracted withchloroform (5×100 ml). The chloroform extracts were concentrated to givethe free base which was purified on a column of silica gel by elutionwith chloroform-methanolic ammonia. After treatment with an excess ofethanolic hydrogen chloride, the residue was triturated withacetonitrile to give the title compound (2.5 g), m.p. 182°-185°.

(Found: C, 35.8; H, 6.3; N, 21.2; Cl, 21.3; S, 9.5%. C₁₀ H₁₉ N₅ OS. 2HCl requires: C, 36.4; H, 6.4; N, 21.2; Cl, 21.5; S, 9.7%).

EXAMPLE 4N-Methoxy-N',N"-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinetrihydrochloride

A mixture of the isothiourea trihydrochloride from Example 2(ii) (5.1g), methoxyamine hydrochloride (2.5 g), potassium hydrogen carbonate(5.0 g) and water (30 ml) was refluxed for 24 hours. The products werepartitioned between N sodium hydroxide and n-butanol. The n-butanolsolution was then extracted with N hydrochloric acid, and the extractsconcentrated and dissolved in isopropanol. After filtration frominorganic material, the filtrate gave the title compound (0.6 g). When asolution in aqueous ethanol of this compound was eluted from an ionexchange column of IRA-401 in nitrate form, the corresponding trinitratewas obtained. n.m.r. spectrum (D₂ O):

δ 2.38 (singlet), 6H, Imidazole -- CH₃

δ 2.85 (triplet, J=7H₂), 4H, S-CH₂ --CH₂

δ 3.53 (triplet, J=7H₂), 4H, N-CH₂ --CH₂

δ 3.83 (singlet), 3H, O-CH₃

δ 3.97 (singlet), 4H, Imidazole -- CH₂ -- S

δ 8.87 (singlet), 2H, Imidazole -- H

EXAMPLE 5N-Amino-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride.

A mixture of the isothiourea dihydrochloride from Example 1(i) (8.3 g),hydrazine sulphate (4.1 g), potassium hydrogen carbonate (12.5 g) andanhydrous dimethyl formamide (100 ml) was stirred at 90° C. for 3 hours.Following cooling and filtration from inorganic material, the filtratecontaining the free base was treated with ethanolic hydrogen chloride.The residue was then triturated with isopropanol to give a solid whichwas recrystallised from aqueous isopropanol to give the title compound(1.94 g), m.p. 234°-235°.

(Found: C, 34.0; H, 6.4; N, 26.2; Cl, 22.2; S, 10.0%. C₉ H₁₈ N₆ S. 2HClrequires: C, 34.3; H, 6.4; N, 26.7; Cl, 22.5; S, 10.2%)

EXAMPLE 6N-Amino-N',N"-bis[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinetrihydrochloride.

A mixture of the isothiourea trihydrochloride from Example 2(ii) (5.1g), hydrazine sulphate (1.6 g), potassium hydrogen carbonate (7.0 g) andanhydrous dimethyl formamide (60 ml) was stirred at 70° for 3 hours.Following cooling and filtration the filtrate containing the free basewas treated with an excess of ethanolic hydrogen chloride to give thetitle compound.

EXAMPLE 7N-Hydroxy-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidinedihydrochloride

(i) Methyl iodide (5 ml) was added to a solution ofN-methyl-N'-[2-(2-thiazolylmethylthio)ethyl]thiourea (4.7 g) in methanol(50 ml), and the mixture was refluxed for 10 minutes. The products wereconcentrated and treated with ion-exchange resin IRA-401 (Cl⁻) followedby an excess of ethanolic hydrogen chloride. Concentration of thissolution gaveN,S-dimethyl-N'-[2-(2-thiazolylmethylthio)ethyl]isothioureadihydrochloride (5.6 g).

(ii) A mixture of the isothiourea dihydrochloride (0.46 g),hydroxylamine hydrochloride (0.35 g), potassium hydrogen carbonate (1.5g) and anhydrous dimethyl formamide (10 ml) was stirred at 90° for 4hours. The products were partitioned between chloroform and water, thechloroform evaporated to yield the free base and this was treated withan excess of ethanolic hydrogen chloride. After concentration, theresidue was triturated with isopropanol to give the title compound (0.10g), m.p. 171°-174°. n.m.r. spectrum ² H₆ dimethyl sulphoxide:

δ 2.78 (doublet, J = 5H₂), 3H, NH-CH₃

δ 3.12 (multiplet), 2H, S-CH₂ -CH₂

δ 3.49 (multiplet), 2H, N-CH₂ -CH₂

δ 4.36 (singlet), 2H, Thiazole-CH₂ -S

δ 7.90 (multiplet), 2H, Thiazole-2H

δ 7.98 (multiplet), 2H, -NH-CNOH-NH-

δ 9.24 (broad singlet), 1H, -O-H

EXAMPLE 8N-Methyl-N'-methylamino-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride

A mixture of the isothiourea dihydrochloride of Example 1 (i) (6.7 g),N-methyl-N-tert-butoxycarbonylhydrazine sulphate (5.7 g), potassiumhydrogen carbonate (10.0 g) and anhydrous dimethylformamide (80 ml) wasstirred at 90° C. for 3 hours. After cooling, filtration andconcentration to yield the free base, this was heated under reflux withethanolic hydrogen chloride. Concentration and trituration of theresidual product yielded the title compound.

EXAMPLE 9N-Methyl-N'-hydroxy-N"-[3-((4-methyl-5-imidazolyl)methylthio)propyl]guanidinedihydrochloride.

Reaction ofN-methyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)-propyl]thiourea withmethanolic hydrogen chloride by the method of Example 1(i) yieldedN,S-dimethyl-N'-[3-((4-methyl-5-imidazolyl)methylthio)propyl]isothioureadihydrochloride which on treatment with hydroxylamine by the procedureof Example 1(ii) gave the title product.

EXAMPLE 10N-Methyl-N'-hydroxy-N"-[4-(4-imidazolyl)butyl]guanidine-dihydrochloride.

When N-methyl-N'-[4-(4-imidazolyl)butyl]thiourea is reacted withmethanolic hydrogen chloride by the procedure of Example 1(i) theproduct is N,S-dimethyl-N'-[4-(4-imidazolyl)butyl]isothiourea which ontreatment with hydroxylamine by the procedure of Example 1(ii) gives thetitle product.

EXAMPLE 11 N-Methyl-N'-hydroxy-N"-[4-(2-thiazolyl)butyl]guanidinedisulphate

N-Methyl-N'-[4-(2-thiazolyl)butyl]thiourea was converted into itshydriodide salt with 66% hydriodic acid. This salt was dissolved inmethanol, methyl iodide added and the solution heated under reflux for 2hours. Concentration and crystallisation of the resultant oil gaveN,S-dimethyl-N'-[4-(2-thiazolyl)butyl]isothiourea dihydriodide. Reactionof this isothiourea with hydroxylamine by the procedure of Example 1(ii)gave the title product.

EXAMPLE 12N-Methyl-N'-hydroxy-N"-[2-((3-chloro-2-pyridyl)methylthio)ethyl]guanidinedinitrate

By the procedure of Example 1(i),N-methyl-N'-[2-((3-chloro-2-pyridyl)methylthio)ethyl]thiourea wasconverted toN,S-dimethyl-N'-[2-((3-chloro-2-pyridyl)methylthio)ethyl]isothioureadihydrochloride which, on reaction with hydroxylamine by the procedureof Example 1(ii) yielded the title product.

EXAMPLE 13N-Methyl-N'-phenoxy-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride

Reaction of the isothiourea dihydrochloride produced by Example 1(i)with phenoxyamine by the procedure of Example 1(ii) gave the titleproduct.

EXAMPLE 14N-Methyl-N'-benzyloxy-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride

Reaction of the isothiourea dihydrochloride of Example 1(i) withbenzyloxyamine by the procedure of Example 1(ii) gave the title product.

EXAMPLE 15

Reaction of the following isothiourea dihydrochlorides (prepared fromthe corresponding thioureas by the procedure of Example 1(i):

(a) N,S-dimethyl-N'-[2-((3-isothiazolyl)methylthio)ethyl]-isothioureadihydrochloride

(b) N,S-dimethyl-N'-[3-(2-oxazolyl)thiopropyl)isothioureadihydrochloride

(c) N,S-dimethyl-N'-[2-((3-isoxazolyl)methylthio)ethyl]-isothioureadihydrochloride

(d) N,S-dimethyl-N'-[2-((3-1,2,4-triazolyl)methylthio)ethyl]-isothioureadihydrochloride

(e)N,S-dimethyl-N'-[2-((5-amino-2-1,3,4-thiadiazolyl)-methylthio)ethyl]isothioureadihydrochloride

(f)N,S-dimethyl-N'-[2-((3-hydroxy-2-pyridyl)methylthio)ethyl]-isothioureadihydrochloride

(g) N,S-dimethyl-N'-[2-((3-bromo-2-pyridyl)methylthio)ethyl]-isothioureadihydrochloride

(h)N,S-dimethyl-N'-[2-(2-(4-methyl-5-imidazolyl)ethylthio)-ethyl]isothioureadihydrochloride with hydroxylamine according to the procedure of Example1(ii) yields the following products:

(a)N-hydroxy-N'-methyl-N"-[2-((3-isothiazolyl)methylthio)ethyl]guanidinedihydrochloride

(b) N-hydroxy-N'-methyl-N"-[3-((2-oxazolyl)thiopropyl]guanidinedihydrochloride

(c) N-hydroxy-N'-methyl-N"-[2-((3-isoxazolyl)methylthio)-ethyl]guanidinedihydrochloride

(d)N-hydroxy-N'-methyl-N"-[2-((3-1,2,4-triazolyl)methylthio)-ethyl]guanidinedihydrochloride

(e)N-hydroxy-N'-methyl-N"-[2-((5-amino-2-1,3,4-thiadiazolyl)-methylthio)ethyl]guanidinedihydrochloride

(f)N-hydroxy-N'-methyl-N"-[2-((3-hydroxy-2-pyridyl)methylthio)-ethyl]guanidinedihydrochloride

(g)N-hydroxy-N'-methyl-N"-[2-((3-bromo-2-pyridyl)methylthio)-ethyl]guanidinedihydrochloride

(h)N-hydroxy-N'-methyl-N"-[2-(2-(4-methyl-5-imidazolyl)-ethylthio)ethyl]guanidinedihydrochloride.

EXAMPLE 16

Reaction of the isothiourea dihydrochloride of Example 1(i) withn-propoxyamine and n-butyoxyamine according to the procedure of Example1(ii) gave respectivelyN-methyl-N'-n-propoxy-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride andN-methyl-N'-n-butoxy-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride.

EXAMPLE 17

Reaction of the following isothiourea salts (prepared from thecorresponding thioureas by the procedure of Example 1(i):

(a) S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-isothioureadihydrochloride

(b) S-methyl-N-n-butyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]isothiourea dihydrochloride

(c)S-methyl-N-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N'-[2-((2-thiazolyl)methylthio)ethyl]isothioureatrihydrochloride, with hydroxylamine according to the procedure ofExample 1 (ii) yields the following products:

(a) N-hydroxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-guanidinedihydrochloride

(b)N-hydroxy-N'-n-butyl-N"-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidinedihydrochloride

(c)N-hydroxy-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-N"-[2-((2-thiazolyl)methylthio)ethyl]guanidinetrihydrochloride.

EXAMPLE 18

    ______________________________________                                        Ingredients                 Amounts                                           ______________________________________                                        N-Hydroxy-N'-methyl-N"-[2-((4-methyl-5-                                       imidazolyl)methylthio)ethyl]guanidine dihydro-                                                            150 mg                                            chloride                                                                      Sucrose                     75 mg                                             Starch                      25 mg                                             Talc                        5 mg                                              Stearic Acid                2 mg                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 19

    ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        N-Hydroxy-N,N'-bis-[2-((4-methyl-5-                                           imidazolyl)methylthio)ethyl]guanidine                                         trihydrochloride         200 mg.                                              Lactose                  100 mg.                                              ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

What we claim is:
 1. A compound of the formula: ##STR5## wherein R₁represents a grouping of the structure shown in the formula:

    Het -- (CH.sub.2).sub.m Z(CH.sub.2).sub.n                  FORMULA II

wherein Het is a nitrogen containing 5 or 6 membered heterocyclic ringsuch as pyridine which is optionally monosubstituted by lower alkyl,hydroxyl, chlorine or bromine, 1,2,4-triazole, 1,3,4-thiadiazole or2-amino-1,3,4-thiadiazole; Z is sulphur or a methylene group; m is 0, 1or 2 and n is 2 or 3 provided that the sum of m and n is 3 or 4; R₂ ishydrogen, lower alkyl or a grouping of the structure shown in Formula IIwherein Het, m, n and Z are as defined above; X is oxygen or when R₂ isa grouping of the structure shown in Formula II, X may be NH; and R₃ ishydrogen, lower alkyl, phenyl or benzyl, or a pharmaceuticallyacceptable acid addition salt thereof.
 2. A compound of claim 1 whereinX is oxygen and R₃ is hydrogen.
 3. A compound of claim 1 wherein R₂ islower alkyl.
 4. A compound of claim 1 wherein R₂ is the same as R₁.
 5. Acompound of claim 1 wherein m is 1 and n is
 2. 6. A compound of claim 1wherein Z is sulphur.
 7. A compound of claim 1 wherein Het is pyridineoptionally substituted by methyl, hydroxyl, chlorine or bromine.
 8. Apharmaceutical composition to block histamine H₂ -receptors comprising apharmaceutically acceptable diluent or carrier and, in an effectiveamount to block said receptors, a compound of claim
 1. 9. A method ofblocking histamine H₂ -receptors which comprises administering to ananimal in need thereof in an effective amount to block said receptors acompound of claim
 1. 10. A method of inhibiting gastric acid secretionwhich comprises administering to an animal in need thereof in aneffective amount to inhibit gastric acid secretion a compound of claim1.